The bombesin/gastrin releasing peptide (GRP) receptor system, i.e. bombesin/gastrin, their receptors and the components of the receptor-mediated signaling pathways, is known to be involved in the regulation of several aspects of CNS function (Yamada et al., Mol. Psychiatry 7, 113-117 (2002)), in neuropsychiatric disorders, such as schizophrenia (Mellar et al., Peptides 25, 585-588 (2004)) and autism (Ishikawa-Brush et al., Hum. Mol. Genet. 6, 1241-1250 (1997)), in the development of cancer (Schwartsmann, G., Lung Cancer 46, 129 (2004); Szepeshazi et al., Proc. Natl. Acad. Sci. U.S.A. 94, 10913 (1997)), and in the pathogenesis of chronic bronchitis (Meloni et al., Int. J. Tissue React. 14, 195-201 (1992)) and pulmonary fibrosis (Lemaire et al., Neuropeptides 20, 63-72 (1991)).
It is further known that the bombesin/GRP system has several effects on the immune system. For example, GRP has been reported to induce mast cell proliferation and chemotaxis in vitro (Genton et al., American Journal of Surgery 186, 253-258 (2003); Subramaniam et al., Am. J. Respir. Crit. Care Med. 168, 601-611 (2003)) and to modulate, as a stimulator or inhibitor, the function of lymphocytes, phagocytes and natural killer cells (Medina et al., Mechanisms of Ageing and Development 102, 249-261 (1998); Medina et al., Neuropeptides 33, 173-179 (1999); De la Fuente et al., Immunology 73, 205-211 (1991); Medina et al., Neuropeptides 32, 549-555 (1998)). Furthermore, GRP seems to have stimulatory effects on mobility, ingestion and superoxide production in macrophages from adult mice, potentiating IL-1 release by alveolar macrophages activated with lipopolysaccharide (LPS) (De la Fuente et al., Life Sciences 67, 2125-2135 (2000); De la Fuente et al., Immunology73, 205-211 (1991); Lemaire et al., Neuropeptides 20, 217-223 (1991)).
Although the exact intracellular pathways associated with the above-mentioned GRP-related effects remain to be identified it has been reported that certain GRP effects on murine peritoneal leukocytes are mediated through the activation of protein kinase C (Del Rio et al., Regul. Pept. 49, 185-193 (1994)). Further, it is known that bombesin, a homolog of GRP, stimulates cyclooxygenase-2 (COX-2) expression in intestinal epithelial cell lines. The bombesin-stimulated COX-2 expression requires an increase in [Ca+2], the activation of extracellular signal-regulated kinase (ERK)-1 and -2 and p38MAPK, and the increased activation and expression of the transcription factors Elk-1, ATF-2, c-Fos, and c-Jun (Guo Y.-S. et al., J. Biol. Chem. 276, 22941-22947 (2001)).
Over the past few years, the bombesin/GRP receptor system has emerged as a promising drug target for anticancer therapy (Schwartsmann, G., Lung Cancer 46, 129 (2004); Szepeshazi et al., Proc. Natl. Acad. Sci. U.S.A. 94, 10913 (1997), U.S. Pat. Nos. 5,244,883 and 5,369,094) and neuropsychiatric disorders (Ishikawa-Brush et al., Hum. Mol. Genet. 6, 1241-1250 (1997); and Mellar et al., Peptides 25, 585-588 (2004)) and great efforts have been directed to the development of bombesin/GRP antagonists. Today, several kinds of bombesin/GRP antagonists are known, which mainly belong to the class of polypeptide compounds. Examples thereof include nonapeptide compounds disclosed in U.S. Pat. No. 5,244,883, nonapeptide compounds disclosed in U.S. Pat. No. 5,369,094, analogues of substance P (Coy et al., J. Biol. Chem. 263, 5056 (1988)), and analogues of GRP(20-27) (Heimbrook et al., J. Biol. Chem. 264, 11258 (1989)).
The therapeutic potential of bombesin/GRP antagonists to improve inflammatory and immune-mediated inflammatory conditions, in particular septic shock and acute lung injury, however, is still unknown. The occurence of (systemic) inflammations is a serious problem associated with numerous medical conditions and is assumed to be the cause of death in many cases. The anti-inflammatory strategies available today, however, produce only modest clinical effects in critically ill patients (BLUE Journal). This could be secondary to several factors, including the heterogeneous inflammatory response associated with these conditions (Hotchkiss & Karl, New Engl. J. Med. 348, 138-150 (2003)) and the misleading design of pre-clinical studies (Ritter et al., Lancet 364, 498-499 (2004); Polderman et al., Lancet 363, 1721-1723 (2004)).
Septic shock, for example, has become one of the most frequent causes of morbidity and mortality in intensive care units (Sands et al., JAMA 278, 234-240 (1997)). Although commonly initiated by an infection, the pathogenesis of sepsis is characterized by an overwhelming systemic inflammatory response that can lead to lethal multiple organ failure (Hotchkiss & Karl, New Engl. J. Med. 348, 138-150 (2003)). Conventional treatment of sepsis consists of supporting blood pressure, organ blood flow and ventilation, along with an emphasis on antibiotics and eradicating the source(s) of infection. Despite significant advances in the understanding of pathogenesis of sepsis and its management, the mortality from septic shock has improved little over the last several decades (Friedman et al., Crit Care Med. 26, 2078-2086 (1998)).
Bipolar disorder, also known as manic-depressive illness, is a brain disorder that causes unusual shifts in a person's mood, energy, and ability to function. Different from the normal ups and downs that everyone goes through, the symptoms of bipolar disorder are severe. They can result in damaged relationships, poor job or school performance, and even suicide. A comprehensive overview about bipolar disorder and further references can be found in National Institute of Mental Health (NIMH) publication “Bipolar disorder”, NIH Publication No. 02-3679, Printed 2001, Reprinted September 2002, which is also available at http://www.nimh.nih.gov/publicat/NIMHbipolar.pdf.
More than 2 million American adults, or about 1 percent of the population age 18 and older in any given year, have bipolar disorder. Bipolar disorder typically develops in late adolescence or early adulthood. However, some people have their first symptoms during childhood, and some develop them late in life. It is often not recognized as an illness, and people may suffer for years before it is properly diagnosed and treated. Like diabetes or heart disease, bipolar disorder is a long-term illness that must be carefully managed throughout a person's life.
Bipolar disorder causes dramatic mood swings—from overly “high” and/or irritable to sad and hopeless, and then back again, often with periods of normal mood in between. Severe changes in energy and behavior go along with these changes in mood. The periods of highs and lows are called episodes of mania and depression.
Signs and symptoms of mania (or a manic episode) include “Increased energy, activity, and restlessness; Excessively “high,” overly good, euphoric mood; Extreme irritability; Racing thoughts and talking very fast, jumping from one idea to another; Distractibility, can't concentrate well; Little sleep needed; Unrealistic beliefs in one's abilities and powers; Poor judgment; Spending sprees; A lasting period of behavior that is different from usual; Increased sexual drive; Abuse of drugs, particularly cocaine, alcohol, and sleeping medications; Provocative, intrusive, or aggressive behavior; Denial that anything is wrong”.
A manic episode is diagnosed if elevated mood occurs with three or more of the other symptoms most of the day, nearly every day, for 1 week or longer. If the mood is irritable, four additional symptoms must be present.
Signs and symptoms of depression (or a depressive episode) include “Lasting sad, anxious, or empty mood; Feelings of hopelessness or pessimism; Feelings of guilt, worthlessness, or helplessness; Loss of interest or pleasure in activities once enjoyed, including sex; Decreased energy, a feeling of fatigue or of being “slowed down”; Difficulty concentrating, remembering, making decisions; Restlessness or irritability; Sleeping too much, or can't sleep; Change in appetite and/or unintended weight loss or gain; Chronic pain or other persistent bodily symptoms that are not caused by physical illness or injury; Thoughts of death or suicide, or suicide attempts”.
A depressive episode is diagnosed if five or more of these symptoms last most of the day, nearly every day, for a period of 2 weeks or longer.
A mild to moderate level of mania is called hypomania. Hypomania may feel good to the person who experiences it and may even be associated with good functioning and enhanced productivity. Thus even when family and friends learn to recognize the mood swings as possible bipolar disorder, the person may deny that anything is wrong. Without proper treatment, however, hypomania can become severe mania in some people or can switch into depression.
Sometimes, severe episodes of mania or depression include symptoms of psychosis (or psychotic symptoms). Common psychotic symptoms are hallucinations (hearing, seeing, or otherwise sensing the presence of things not actually there) and delusions (false, strongly held beliefs not influenced by logical reasoning or explained by a person's usual cultural concepts). Psychotic symptoms in bipolar disorder tend to reflect the extreme mood state at the time. For example, delusions of grandiosity, such as believing one is the President or has special powers or wealth, may occur during mania; delusions of guilt or worthlessness, such as believing that one is ruined and penniless or has committed some terrible crime, may appear during depression. People with bipolar disorder who have these symptoms are sometimes incorrectly diagnosed as having schizophrenia, another severe mental illness.
It may be helpful to think of the various mood states in bipolar disorder as a spectrum or continuous range. At one end is severe depression, above which is moderate depression and then mild low mood, which many people call “the blues” when it is short-lived but is termed “dysthymia” when it is chronic. Then there is normal or balanced mood, above which comes hypomania (mild to moderate mania), and then severe mania.
In some people, however, symptoms of mania and depression may occur together in what is called a mixed bipolar state. Symptoms of a mixed state often include agitation, trouble sleeping, significant change in appetite, psychosis, and suicidal thinking. A person may have a very sad, hopeless mood while at the same time feeling extremely energized.
Bipolar disorder may appear to be a problem other than mental illness—for instance, alcohol or drug abuse, poor school or work performance, or strained interpersonal relationships. Such problems in fact may be signs of an underlying mood disorder.
The prevalence, high risk for suicide and social and economic costs reveal bipolar disorder as a major public health hazard.
There is a need, therefore, for alternative medicaments for the treatment of inflammatory and immune-mediated inflammatory conditions, such as sepsis and acute lung injury, as well as bipolar disorder.